This is a proposal to develop new strategies, concepts, and methods applicable to the chemical synthesis of biologically active natural products and their structural analogs. These discoveries will be applicable to the synthesis of other pharmaceutically relevant compounds as well. Access to (often simpler) analogs of the natural products themselves will result. These will be evaluated in an attempt to identify the structural elements comprising the minimum pharmacophore. Aim I. Capitalize on our substantial body of "in house" expertise with xestospongin C (XeC, I), a potent, membrane permeable inhibitor of intracellular inositol triphosphate (IP3) induced Ca++ release. Develop variants of XeC (including xestospongin 0) as potentially valuable probes for study of calcium release. Aim II. Study the reactivity and stability of the novel acyclic Beta-acyloxy carbinolamide functionality as well as new methods for macrocyclization (epoxide/acid ring opening and a tandem macrocyclization/ring contraction of acylated oximes) during the synthesis of zampanolide (II). Aim III. Develop the power of our newly discovered relay ring-closing metathesis (RRCM) strategy in its application to a synthesis of oocydin A/haterumalide NA (III), an independently discovered agent isolated from two quite different organisms, which possesses remarkable antifungal and antiproliferative properties. Aim IV. Take advantage of a powerful kinetic lactonization in the desymmetrization of a key intermediate and demonstrate additional features of RRCM in the course of synthesizing the recently isolated, structurally novel macrolide, peloruside A (IV).